The Bridge Between Transplantation and Regenerative Medicine: Beginning a New Banff Classification of Tissue Engineering Pathology

Received: 28 April 2017 | Revised: 21 November 2017 | Accepted: 24 November 2017 DOI: 10.1111/ajt.14610

PERSONAL VIEWPOINT

The bridge between transplantation and regenerative medicine: Beginning a new Banff classification of tissue engineering pathology

1Department of Laboratory Medicine and Pathology, Faculty of Medicine and The science of regenerative medicine is arguably older than transplantation—the first Dentistry, University of Alberta, Edmonton, major textbook was published in 1901—and a major regenerative medicine meeting AB, Canada took place in 1988, three years before the first Banff transplant pathology meeting. 2Medical Anthropology Program, Department of Anthropology, Faculty of Arts and However, the subject of regenerative medicine/tissue engineering pathology has Sciences, University of Toronto, Toronto, never received focused attention. Defining and classifying tissue engineering pathol- Ontario, Canada ogy is long overdue. In the next decades, the field of transplantation will enlarge at 3Division of Urology GOFARR Laboratory for Organ Regenerative Research and least tenfold, through a hybrid of tissue engineering combined with existing ap- Cell Therapeutics, Children’s Hospital Los proaches to lessening the organ shortage. Gradually, transplantation pathologists will Angeles, Saban Research Institute, University of Southern California, Los Angeles, CA, USA become tissue-(re-) engineering pathologists with enhanced skill sets to address con- 4Department of Surgery, Johns Hopkins cerns involving the use of bioengineered organs. We outline ways of categorizing ab- School of Medicine, Baltimore, MD, USA normalities in tissue-engineered organs through traditional light microscopy or other 5Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA modalities including biomarkers. We propose creating a new Banff classification of 6Department of Pathology, University of tissue engineering pathology to standardize and assess de novo bioengineered solid Pittsburgh, UPMC-Montefiore, Pittsburgh, organs transplantable success in vivo. We recommend constructing a framework for a PA, USA classification of tissue engineering pathology now with interdisciplinary consensus 7Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA discussions to further develop and finalize the classification at future Banff Transplant Pathology meetings, in collaboration with the human cell atlas project. A possible no- Correspondence K. Solez sology of pathologic abnormalities in tissue-engineered organs is suggested. Email: [email protected]

KEYWORDS Funding information Roche Organ Transplantation Research bioengineering, biomarker, biopsy, cellular transplantation (non-islet), classification systems: Foundation, Grant/Award Number: Banff classification, editorial/personal viewpoint, pathology/histopathology, regenerative 608390948 medicine, tissue injury and repair, translational research/science

1 | INTRODUCTION 10% of this number. Regenerative medicine/tissue engineering can re- habilitate suboptimal donor organs, thereby considerably expanding Worldwide approximately 1.2 million people need transplantation for the current donor organ pool, and has the potential to save the re- end stage organ failure.1 Current transplant protocols reach fewer than maining 90%, by generating or repairing organs. Rapid advances are

Abbreviations: HCAP, Human cell atlas project; TEP, Tissue engineering pathology; TET, Tissue engineering transplantation.

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2017 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons

Am J Transplant. 2018;18:321–327. amjtransplant.com | 321 322 | SOLEZ et al. also being made in other areas to increase the donor pool, including monitoring after transplantation will be crucial to the success of this xenotransplantation,2 tolerance induction,3 ex vivo perfusion,4 organ new medical discipline. Some of this monitoring will be via soluble preservation and banking,5 and more traditional approaches.6 If the biomarkers,7 or possibly employing implantable sensors as well as by field of transplantation is to be increased tenfold or more in size to fill more traditional pathology techniques. the expanding need for organ replacement, regenerative medicine will In this paper, we define a new pathology discipline, tissue engineering be the major cause of this improvement, but there will be many other pathology, and propose a basic construct for a new Banff classification of secondary causes in addition. A hybrid of these different modalities this new discipline, with the aim of having the first full version of the clas- working in concert is likely the most appropriate model for the future sification finalized through consensus discussions at the 2021, 2023, and of transplantation, with tissue engineering/regenerative medicine ap- 2025 Banff allograft pathology meetings. It will be along organ lines, simi- proaches eventually becoming the dominant approach (Table 1). lar to the current Banff classification scheme8–10 but with a focus entirely The future safety and efficacy of bioengineered tissues and organs separate from the current scheme. Since it is likely that the new Tissue is crucial to long-term transplantation success. It cannot be assumed Engineering Pathology classification will overlap with the current Banff that every rehabilitated or stem cell-generated organ has normal struc- classification for at least a decade, it is important that it be constructed in ture and function and will provide net benefit to the patient. Indeed a fashion that will not be confused with the current Transplant Pathology a first branch point in a taxonomy of engineered organs—be they classification, so both classifications can easily be scored simultaneously. repopulated scaffolds or cells on chips—is distinguishing deviations from a gold standard healthy functioning native organ arising from engineering decisions or problems of generation, versus problems of 2 | HISTORY AND BACKGROUND deterioration in situ. Pathologic examination of organs produced by regenerative medicine/tissue engineering before transplantation and The first publication in transplantation pathology, an article about transplantation of embryo tissue by Nobel laureate Peyton Rous, appeared in TABLE 1 Solutions to the organ shortage—the hybrid 1910.11 The first Banff allograft pathology meeting was in 1991, repre- 2–6,29,32 model —In the likely future of transplantation all these senting the start of the Banff Classification of Transplant Pathology and elements will contribute to solution of the organ shortage but Banff Consensus Meetings.8–10 Remarkable progress in transplantation eventually regenerative medicine/tissue engineering approaches will become the dominant influence. It is not either or. A and B can and pathology has been made over the past 107 years and particularly the will be combined past 26 years. The creation of a Banff Classification of Tissue Engineering would be an important new development in the Banff Consensus Process. A. Initiatives Optimizing/Improving Allotransplantation as It Is The science of regenerative medicine is arguably older than transplan- Practiced Now tation—a first major textbook was published in 1901 by Nobel Laureate Tolerance induction Thomas Hunt Morgan12 and another by Korshelt on regeneration and Presumed consent transplantation in 1927.13 A major tissue engineering/regenerative medi- Paired exchange cine meeting took place in 1988 with proceedings published in 1989.14,15 Xenotransplantation The history of tissue engineering pathology (TEP) goes back to the Cryonic Preservation 1967 article by Hubacek et al. on reaction to scaffold material.16 The use Improved tissue typing of the term “tissue engineering” began in 1988 with an article by Vacanti 15,17 Desensitization therapy et al. co-authored by pathologist Antonio Perez-Atayde. Pathology Use of HIV and HCV positive donors has been part of tissue engineering from its inception but it makes sense Buying organs to delineate TEP as a distinct area of pathology now that clinical trials are commencing and the number of publications is increasing rapidly. Organ donation after euthanasia Clinical trials of encapsulated islet cells are underway18 and trials B. Initiatives Increasing Organ Supply/Repair Capabilities through Regenerative Medicine/Tissue Engineering—Possible Elimination of with a bioartificial kidney with silicon filter and human cells are slated Rejection as a Consideration to start by the end of 2017.19 The range of clinically useful bioengi- Organ scaffolds neered constructs is very broad and even includes vascular conduits 20 3D printed organs for hemodialysis without cells. Stem cell repair of organs in vivo Ex vivo perfusion with stem cell repair | Practical use of organoids 3 REGENERATIVE MEDICINE—TISSUE ENGINEERING TRANSPLANTATION De novo growing of organs simulating embryogenesis (TET) DEFINED Synthetic scaffolds better than natural ones Better understanding of matrix factors Regenerative medicine—tissue engineering transplantation (TET) is the Human cell atlas approaches use of various combinations of bioengineered organs, bio-artificial or- Liquid biopsy approach gans, interventional extra-corporeal normothermic machine perfusion, SOLEZ et al. | 323 techniques to enhance stem cell repair in tissues and xenotransplanta- distances in lungs. Abnormalities of the nerves in engineered tissue tion to solve the problem of organ shortage and tissue repair once and could lead to cardiac arrthymias or seizures from epileptogenic foci for all. These techniques may also hold the promise of reducing or avoid- in the brain. Abnormal growth could lead to teratoma formation or ing rejection, since the organs implanted could be made more or less other malignancies. genetically identical to the recipient, or protected from rejection through The microscopic appearance of bioengineered organs may con- bio-modification or encapsulation. Extra-corporeal perfusion allowing ex tinue to evolve after implantation. Pathologic examination would be vivo repair and rehabilitation of organs to be transplanted is another as- of interest both before implantation and at multiple times after implan- pect of regenerative medicine, as is the production of organoids: simpli- tation. Where frequent biopsies were not practical or safe, information fied organs in miniature created by stem cells or progenitor cells.21 about the evolving state of the organ could be obtained through sol- The number of publications per year in these fields shows that TET uble biomarkers, cytology, and/or intravital microscopy. Morphology is no longer something of the distant future; it is occurring right now could change considerably after implantation, either deteriorating with PubMed “regenerative medicine” publication numbers in 2016 from normal after implant or normalizing from abnormal, which could (6216) nearly doubling those in 2013 (3334). A PubMed search on result from intrinsic or host-derived stem cell differentiation. In vivo words like “Decellularized” shows how the field has evolved over the the matrix used to engineer the organ might undergo complete re- past two decades. Table 2 shows the related regenerative medicine modeling and the cells could behave quite differently from the way standards that exist, in the areas of scaffolds, bioengineered bone, they behaved before implantation. tendon, and meniscus.

5 | TISSUE ENGINEERING PATHOLOGY 4 | TISSUE ENGINEERING PATHOLOGY AND THE 21ST CENTURY CURES ACT (TEP) DEFINED Section 3033 of the United States 21st Century Cures Act states that Similar to traditional transplantation pathology, TEP consists of all a drug is eligible for regenerative medicine advanced therapy (RMAT) possible pathological abnormalities that might be encountered in the designation if it meets certain criteria for efficacy. One can imagine organs or tissues, before, during, or after regenerated organs or tis- tissue engineering pathology scores and standards becoming a part of sues are implanted in a recipient: examples include tissue and immu- submissions requesting such designations. nological reactions to scaffold material, missing cells or cells in the Current approved therapies are shown in Table 3. wrong places, or a cell population that has not had sufficient time to expand and differentiate. Lack of long loops of Henle is common when kidneys are made from re-aggregated fetal cells in animal models22 6 | COMPROMISES—“GOOD ENOUGH and might lead to potentially fatal massive polyuria, but it remains PATHOLOGY” to be seen whether the altered physiology this brings about23 cannot be easily managed by other means. A common challenge across Many abnormalities in bioengineered organs in animals are qualita- all vascularized solid organs “grown” from scaffolding is establishing tively distinct from abnormalities seen in transplanted or native human the microvascular network that will properly support “energy-hungry” organs of today. These often include a microvasculature inadequate to parenchymal cells (cardiac myocytes, hepatocytes, kidney tubular support functional parenchymal cells, missing cells, cells in the wrong cells) and avoid impaired function, as might occur with long diffusion places, misshapen structures, or structures that appear perfect by light microscopy but do not properly function.24,25 As procedural limitations TABLE 2 Regenerative medicine standards related to tissue are overcome, these abnormalities in function and pathology will de- engineering pathology (full references in Supplementary material) crease. Until then, these artifacts must be considered part of the dis-

Optimization and Critical Evaluation of Decellularization Strategies ease classification, with the eventual aim of eliminating them. Remuzzi to Develop Renal Extracellular Matrix Scaffolds as Biological et al.25 highlight “the major physical barriers that limit in vitro recel- Templates for Organ Engineering and Transplantation, Caralt et al., lularization of acellular kidney scaffolds” (getting enough of the right Am J Transplant 15: 64-75, 2015. cells to the right places), “the nonuniform focal cell seeding, and the ASTM F-2529-13 Standard Guide for In Vivo Evaluation of limited cell proliferation with culture time.” We presume these barriers Osteoinductive Potential of Materials Containing Demineralized will be overcome in the next six years and then the nascent Banff clas- Bone. https://www.fda.gov/downloads/BiologicsBloodVaccines/ NewsEvents/WorkshopsMeetingsConferences/UCM434312.pdf sification of tissue engineering pathology will change substantially and outlooks overall will improve. The situation is analogous to the situa- Histopathological scores for tissue-engineered, repaired and degenerated tendon: a systematic review of the literature, Loppini tion that existed in transplantation in the beginning when hyperacute et al., Curr Stem Cell Res Ther 2015;10(1):43-55. rejection was a common threat and immunosuppression was much 26 Histological scoring systems for tissue-engineered, ex vivo and less effective in controlling acute rejection. In an analogous way, the degenerative meniscus, Longo et al., Knee Surg Sports Traumatol present barriers to success will be overcome and then the classifica- Arthrosc. 2013;21(7):1569-1576. tion project this paper describes will be increasingly needed. 324 | SOLEZ et al.

TABLE 3 Cellular products approved in U.S. (References in A Supplementary Material)

A. Licensed Cellular Products

1. Carticel (Autologous Cultured Chondrocytes): For repair of cartilaginous defects of the femoral condyle 2. Provenge (sipuleucel-T): Autologous T-cell immunotherapy for treatment of prostate cancer 3. Laviv (Azficel-T): Autologous fibroblasts for nasolabial fold wrinkles 4. Gintuit (Allogeneic Cultured Keratinocytes and Fibroblasts in bovine collagen): For treatment of mucogingival conditions 5. Maci (Autologous Cultured Chondrocytes on porcine collagen membrane): For repair of cartilage defects of the knee B. Approved Cellular Products (Class III Devices) 6. Dermagraft-TC Organogenesis (Advance Biohealing) PMA/1997 7. Apligraf (Graftskin) Organogenesis PMA/1998 Human keratino- B cytes and fibroblasts as skin substitute 8. OrCel Ortec International PMA & HDE/2001 Allogeneic human skin keratinocytes and fibroblasts as skin substitute 9. Dermagraft Organogenesis (Advance Biohealing) PMA/2001 Cryopreserved human fibroblast-derived dermal substitute 10. Epicel Vericel (Genzyme Biosurgery) HDE/2007 autologous cultured keratinocytes C. Point of Care Device for Cellular Therapy (Class III Device) 11. CliniMACS Miltenyi Biotech, Inc HDE/ 2014 For obtaining CD34 + enriched cells from allogeneic HLA-identical sibling donor for reconstitution in AML patients.

7 | EXAMPLE #1 OF TISSUE ENGINEERING PATHOLOGY, THE DECELLULARIZED RECELLULARIZED RODENT KIDNEY FIGURE 1 A, Pencil sketch by Korey Fung based on Song et al24 image showing misshapen tubule with multiple lumens and missing cells in the glomerulus and interstitium. B, Pencil sketch by Korey “We had quite a few kidneys blow up in the jar” Harald Ott says Fung based on image from Song et al24 showing podocin-positive 24,27 at minute 2:33 of the Nature Medicine video. It never sounded podocytes wandering in the interstitium easy, but those bioengineered rat kidneys that survived the seeding procedure and began functioning had a myriad of morphologic abnormalities that helped shape our thinking about a classification Perin29 are worth of comment. These authors infuse human amnionic of tissue engineering pathology (Figure 1A,B). An important insight fluid stem cells into decellularized discarded human kidney scaffolds is looking at the recellurized organ “from a device perspective” and and then allowed culture periods of up to six weeks. The results sug- thinking about what specific functions it might serve (course video gest that “podocytes wandering in the interstitium” is not just a fea- from minute 9).28 The work of Remuzzi et al25 provides consider- ture of rodent models, but will also be seen with human constructs able additional data on this rat model and suggests that in the first (Figure 2). instance the recellularized organ might be better at filtration than other functions since so many of the cells infused seem to end up in the glomerulus. 9 | A PLAN FOR ACTION

At the 2017 Banff meeting in Barcelona, consideration of TEP mat- 8 | EXAMPLE #2 HUMAN KIDNEY ters was added permanently to the mandate of the individual organ EXTRACELLULAR MATRIX SEEDED WITH chairs for the Banff Transplant Pathology meetings. TEP will be the AMNIONIC FLUID STEM CELLS subject of the day-long pre-meeting that will open the 2019 Banff Meeting in Pittsburgh, September 23-29, 2019. We anticipate the It is of natural interest to see what can be accomplished with human Banff Foundation in the years 2021-2025 will transition to include cells infused into human tissues and so the studies of Petrosyan and this new discipline with specific funding from regenerative medicine SOLEZ et al. | 325

funding agencies and other sources. Regenerative medicine sessions will be included in the Banff meetings and regenerative medicine ex- perts on the Banff Foundation board, to foster collaboration with regenerative medicine organizations such as TERMIS, CTRMS, and the Regenerative Medicine Community of Practice of the AST. We expect the Banff Classification of Tissue Engineering Pathology to be fully evolved and operational by 2027. The focus of tissue engineering pathology will depend on the origin of the regenerated organ. For bio-modified or rehabilitated extended criteria donor organs pathologists may determine whether the desired modification has been achieved (e.g. de-fatting of steatotic liver). For stem cell-derived regenerated organs, questions of tissue reaction and cell growth and differentiation in bioreactors will involve the question of determining with generated whole organs: “Is this organ structurally and functionally intact enough to perform safely and adequately in the recipient?” Using the kidney as an example, the specific questions FIGURE 2 Human amniotic fluid stem cells (AFSC) statically become: seeded onto human adult renal extracellular matrix (ECM) (A. Petrosyan and L. Perin). Analysis (Toluidine Blue staining) of 1. Are the new blood vessels sufficient to sustain the parenchyma? ultra-thin epoxy resin samples of AFSC seeded onto decellularized (This seems to be a major obstacle in many organs.) matrix after 28 d demonstrate the presence of cells throughout the 2. Are too many missing cells and misshapen structures for the organ matrix. Notably the amount of seeded AFSC is limited (due to static to function adequately? (Figure 1A.) seeding) but, interestingly, AFSC acquired different morphology 3. Are there too many cells in the wrong places (e.g. podocytes in the depending on their localization within the decellularized matrix interstitium) (Figure 1B). (such as within the glomerulus where cells AFSC are observed to position on the external layer of the glomerular basement 4. Are there missing structural elements that represent a risk to the membrane similar to in vivo: arrow, 400X). It still unclear if seeded patient? (missing long loops of Henle that could cause lethal polyu- AFSC are differentiated into functional podocytes. Human kidney ria through inability to concentrate the urine, absence of a biliary ECM was kindly provided by Dr. G. Orlando, Wake Forest School drainage system in the liver) (Figure 3). of Medicine Seeding methods are described in references29,31 5. Is there too much endothelial disruption for the organ to be prop- Petrosyan et al. The differentiation of the large cells in the interstitium is unclear but they are somewhat analogous to the erly perfused? “podocytes wandering in the interstitium” in the publication of Song 6. Are there conventional morphological clues that portend neoplastic et al.,24 see Figure 1B transformation?

FIGURE 3 Pencil sketch by Korey Fung showing absence of long loops of Henle (right panel) see Chang and Davies.22 (The original intention was that these three Figures 1A,B and 3 would be redrawn in color by a professional artist in a manner fitting the style of the Journal but time did not permit this.) 326 | SOLEZ et al.

7. Are podocytes able to produce glomerular basement membrane in 10 | THE LARGER CONTEXT: INTEGRATING cooperation with glomerular endothelial cells and is the basement TET WITH PROJECTS SUCH AS THE HUMAN membrane normal enough to allow for satisfactory filtration? This is CELL ATLAS PROJECT AND “LIQUID BIOPSY” the “holy grail” in tissue engineering of the kidney. CIRCULATING DNA DETECTION

One cannot assume that all important questions can be answered It would be ideal if the tissue engineering pathology classification we through routine morphologic examination. Some important questions of create is not something isolated on its own, idiosyncratic, and based stem cell–generated tissue and organ suitability for transplantation may mainly on abnormalities seen in rodent models,24,25,27 but fits within a be best answered through biomarkers (see Supplementary Material)7 or larger human context. A partnership with the newly described human by using genetic analysis, single cell genomics, intravital microscopy, im- cell atlas project of Aviv Regev and Sarah Teichmann would be highly munofluorescence, or electron microscopy. It is not possible to predict in desirable (see Supplemental Material)32 as would a partnership with “liq- advance which modalities of examination will prove to be most import- uid biopsy” systems for detecting circulating DNA in cancer diagnosis.33 ant clinically in the practice of the new discipline of TEP. Indeed, we will The HCAP is described as: likely be exploring structure-function relationships in a whole new way in regenerative medicine transplantation. The first project of its kind, and as ambitious in scope as There are some quantitative concepts that are valuable. The the Human Genome Project, … the HCAP aims to chart the kidney contains more than 26 types of cells.30 In a recent review types and properties of all human cells, across all tissues Petrosyan et al29 asks: Do they all need to be there in a bioengineered and organs, to build a reference map of the … human body. kidney? What are the consequences if they are not? The problems with providing a reliable blood supply for bioengineered constructs Single cell analysis can determine type, state, lineage, location, and are not unlike the difficulties encountered with hyperacute rejection transitions of cells at a rate of 5000 cells a second for a cost approach- in the early days of transplantation.26 The changes were very dra- ing 2.8 cents per cell, with information about DNA, RNA, epigenome, and matic, and occurred rapidly, and some people talked of giving up the protein. This project promises to transform research into human develop- idea of transplantation. But today one never sees hyperacute rejec- ment and the progression of diseases and point the way to new diagnostic tion. It is possible that the blood supply problems of bioengineered tools and treatments. Like all new technologies the HCAP approach will be organs may also be overcome by new scientific advances in the near expensive at first but with widespread application costs will come down. future. The myriad options for cell types, cell delivery, and matrix choices Petrosyan et al have identified29 suggest the need for an artificial intelligence/big data approach to deciding how to construct ACKNOWLEDGMENTS bioengineered organs. Presented in part in keynote presentations at the 2015 Banff Allograft One might also think practically about a more broadly conceptual Pathology meeting in Vancouver and at the 2017 Banff Allograft initial approach, dividing diseases encountered in tissue-engineered Pathology meeting in Barcelona, and as an iPoster from the 2016 organs into those which can also be found in native and transplanted TERMIS meeting in San Diego https://termis.ipostersessions.com/ organs and are in existing classifications, and those pathologies pe- default.aspx?s=78-58-CE-D4-AB-91-46-64-FF-06-6C-A6-54-AD- culiar to the tissue engineered organ. In that latter category, one can 8D-D0 and an iPoster at the 2017 CST/CTRMS meeting in Halifax. divide the changes encountered uniquely in tissue-engineered organs We are grateful to Drs. Aviv Regev and Sarah Teichmann for advice into the following categories, but also distinguishing whether the ab- regarding the Human Cell Atlas collaboration. Supported in part by normality arose in construction of the organ or was acquired later: Roche Organ Transplantation Research Foundation Grant 608390948 1. Normal, no abnormalities found to the Banff Foundation for Allograft Pathology. We thank medical 2. Abnormalities of unknown functional significance student Sina Marzoughi for making suggestions on how to make the 3. Abnormalities which will impair the main functions of the organ paper more accessible and engaging for the general reader. 4. Abnormalities leading to severe organ dysfunction where function may not be great enough to sustain life DISCLOSURE 5. Potential neoplastic abnormalities The authors of this manuscript have no conflicts of interest to disclose Distilled to its essence, an important central idea behind the as described by the American Journal of Transplantation. 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